Aromatic nitriles constitute a key component of numerous commercial compounds including pharmaceuticals, agrochemicals (herbicides, pesticides) and pigments/dyes. For example, The Merck Index, Thirteenth Edition, M. J. O'Neil, Ed. 2001, lists 22 compounds that incorporate this functionality. Their utility also stems from the myriad of possible nitrile transformations including the synthesis of benzoic acids/esters, amidines, amides, imidoesters, benzamidines, amines, heterocycles and aldehydes. The traditional method for preparing aromatic nitriles from the corresponding aryl bromides/iodides, Rosemund-Von Braun reaction, requires stoichiometric copper (I) cyanide at elevated temperatures, often with complicated workups. (For a review, see Mowry, D. T. Chem. Rev. 1948, 42, 189. (b) for improved conditions, see: Friedman, L.; Shechter, H. J. Org Chem. 1961, 26, 2522.) In 1973, Takagi described the first metal-catalyzed cyanation of aryl halides that also happened to be a ligand-free system. (Takagi, K.; Okamoto, T.; Yasumasa, S.; Oka, S. Chem Letters 1973, 5, 471-4.) This methodology employed KCN and 2 mole % Pd(CN)2 (for the aryl bromides substrates) with conversions ranging from 64 to 91% at ≧140° C. Since then, palladium-based methods have garnered most of the attention due to functional group tolerance, air stability and high catalytic activity but none of these methods offered the ligand-free advantage. (For reviews, see: (a) Sundermeier, M.; Zapf, A.; Beller, M. Eur. J. Inorg. Chem. 2003, 3513-3526. (b) Takagi, K., in Handbook of Organopalladium Chemistry for Organic Synthesis (Ed.: Negishi, E.), J. Wiley & Sons: Hoboken, 2002, 1, 657-672.) One constraint of these procedures, which typically use M1—CN (M1=Na, K, TMS, Cu) as the nucleophile, is the high level of dissolved cyanide in the reaction which inhibits the catalytic cycle, namely the oxidative insertion, due to formation of unreactive palladium (II) cyano species. This has led to the use of additives, such as zinc acetate, diamines, zinc dust, Me3SnCl, to enhance the catalytic turnover. (See, Chidambaram, R. Tet. Letters 2004, 1441-1444; Sundmeier, M.; Zapf, A.; Mutyala, S.; Baumann, W.; Sans, J.; Weiss, S.; Beller, M. Chem. Eur. J. 2003, 9, 1828-1836.; Okano, T.; Iwahara, M.; Kiji, J. Synlett 1998, 243; and Yang, C.; Williams, J. M. Org. Letters 2004, 6, 2837-2840.) Controlling the CN concentration via defined dosing of the cyanide has also been used towards this end, as has the use of less soluble cyanide reagents such as zinc cyanide and potassium ferrocyanide (II) (K4[Fe(CN)6]). (For TMS-CN: Sundmeier, M.; Mutyala, S.; Zapf, A.; Spannenberg, A.; Beller, M. J. Organomet. Chem. 2003, 684, 50-55. For acetone cyanohydrin: Sundermeier, M.; Zapf, A.; Beller, M. Angew, Chem. Int. Ed. 2003, 42, 1661. The use of zinc cyanide in this capacity was introduced by: Tschaen, D. M.; Desmond, R.; King, A. O.; Fortin, M. C.; Pipik, B., King, S.; Verhoeven, T. R. Synth. Commun. 1994, 24, 887-890. Also see, Schareina, T.; Zapf, A.; Beller, M. Chem. Commun. 2004, 12, 1388; where we observed no need to dehydrate (3 equiv water present) this reagent as was described by the authors in this article. The latter reagent, potassium hexacyanoferrate (II), recently re-discovered as cyanide source by Beller, is particularly intriguing as all six CN are available for reaction, and it is inexpensive, easily handled and non-toxic. The use of ligands was thought to improve the catalytic activity, and allowed for milder reaction conditions and the inclusion of typically unreactive aryl chlorides. The phosphine ligands though are often air/moisture-sensitive, more costly than the palladium species and difficult to remove from the product and to recover. This has led to a re-examination of the role of ligands in Pd-catalyzed aromatic substitution reactions, as evidenced by recent work describing ligand-free Heck, Suzuki, and Sonogashira reactions. ((a) de Vries, A. H. M., Mulders, J. M. C. A., Mommers, J. H. M., Henderickx, H. J. W., de Vries J. G. Org. Letters 2003, 5, 3285-3288; Reetz, M. T., de Vries J. G. Chem. Commun. 2004, 1559-1563; de Vries J. G., de Vries, A. H. M. Eur. J. Org. Chem. 2003, 799; Urgaonkar, S., Verkade, J. G. J. Org. Chem. 2004, 69, 5752-5755.) As noted by Beletskaya, “the inherent reactivity of unligated palladium is sufficient for oxidative addition to most kinds of C—X bonds.” Beletskaya, I. P; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009-3066. This prompted a study into the potential for similar reactivity with the aromatic cyanation reaction. The present invention is directed to a practical, optionally ligand-ree cyanation of aryl bromides using low loadings of ligand-free palladium.
We have developed a practical, ligand-free aryl cyanation methodology utilizing inexpensive, easy-to handle and non-toxic reagents. This procedure gives high yields for a respectable variety of aryl bromides and is amendable to large scale work as the reactions are rapid and require only a modest catalyst charge. This result adds to the growing list of metal-catalyzed reactions that can be performed ligand-free.